• James W Murrough, Elizabeth Wade, Sehrish Sayed, Gabriella Ahle, Drew D Kiraly, Alison Welch, Katherine A Collins, Laili Soleimani, Dan V Iosifescu, and Dennis S Charney.
• Mood and Anxiety Disorders Program, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States. Electronic address: james.murrough@mssm.edu.
• J Affect Disord. 2017 Aug 15; 218: 277-283.

BackgroundAt least one-third of patients with major depressive disorder (MDD) have treatment-resistant depression (TRD), defined as lack of response to two or more adequate antidepressant trials. For these patients, novel antidepressant treatments are urgently needed.MethodsThe current study is a phase IIa open label clinical trial examining the efficacy and tolerability of a combination of dextromethorphan (DM) and the CYP2D6 enzyme inhibitor quinidine (Q) in patients with TRD. Dextromethorphan acts as an antagonist at the glutamate N-methyl-d-aspartate (NMDA) receptor, in addition to other pharmacodynamics properties that include activity at sigma-1 receptors. Twenty patients with unipolar TRD who completed informed consent and met all eligibility criteria we enrolled in an open-label study of DM/Q up to 45/10mg by mouth administered every 12h over the course of a 10-week period, and constitute the intention to treat (ITT) sample. Six patients discontinued prior to study completion.ResultsThere was no treatment-emergent suicidal ideation, psychotomimetic or dissociative symptoms. Montgomery-Asberg Depression Rating Scale (MADRS) score was reduced from baseline to the 10-week primary outcome (mean change: -13.0±11.5, t19=5.0, p<0.001), as was QIDS-SR score (mean change: -5.9±6.6, t19=4.0, p<0.001). The response and remission rates in the ITT sample were 45% and 35%, respectively.LimitationsOpen-label, proof-of-concept design.ConclusionsHerein we report acceptable tolerability and preliminary efficacy of DM/Q up to 45/10mg administered every 12h in patients with TRD. Future larger placebo controlled randomized trials in this population are warranted.Copyright © 2017 Elsevier B.V. All rights reserved.

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